Fortunately, most men diagnosed with prostate cancer (PCa) will not die from their disease, and some men diagnosed may not even require treatment for their cancers. However, on the other end of the spectrum, ~30,000 men annually die from PCa in the US alone. For these latter men, the concept of PCa as an indolent disease obviously does not apply. Understanding the molecular basis of aggressive PCa (aPCa) vs. indolent PCa (non-aPCa) is perhaps the most important basic, yet translational question in PCa biology. We hypothesize that multiple sequence variants in the genome confer risk to aPCa but not to non-aPCa. Taking advantage of the publicly available CGEMS genome wide association data, as well as the large and unique PCa patient population at Johns Hopkins Hospital (JHH), we propose a systematic genetic association study to confirm, fine map, and better characterize genetic risk variants for aPCa. We propose three specific aims: 1)Test the genetic variants implicated in the CGEMS study that distinguish aPCa from non-aPCa among ~3,000 aPCa and ~5,000 non-aPCa patients of European ancestry from the JHH, 2) Fine map the genomic regions for the SNPs implicated in Aim 1 among 3,000 aPCa and 5,000 non-aPCa patients of European ancestry from the JHH, and 3) Assess the association of the most significant SNPs found in Aim 2 with disease characteristics in all 8,000 patients, and with disease progression in a subset of patients that have follow-up data at JHH. In addition, we have two exploratory aims: 1) fine mapping of regions containing SNPs significant in European Americans in aPCa and non-aPCa in African Americans, and 2) testing for gene-gene interaction. Besides the obvious clues that the proposed research may provide in terms of etiologic mechanisms, this study may also lead to identification of new target genes and proteins for therapy and possible preventive strategies. Furthermore, the identification of multiple variants can lead to the development of a test panel that may improve prediction of aPCa risk. PUBLIC HEALTH RELEVANCE: Prostate cancer is a common cancer that varies widely in its aggressiveness. The ability to predict which men are at risk for the development of aggressive prostate cancer is urgently needed. This proposal addresses the possibility that genetic variants may differentiate risk for aggressive from non-aggressive prostate cancer and the results can be used to predict men at higher risk for aggressive prostate cancer.